The two objectives of this application are to support training of a physician as a medical scientist and to contribute to the basis understanding of human cancer. Dr. Simons aspires to take a clinical education from this medical residency at Massachusetts General Hospital and fellowship in medical oncology at John Hopkins into a career of independent scholarship in oncology. Towards these ends, Dr. Simons will train as a post-doctoral fellow in the Laboratory of Molecular Genetics of the John Hopkins Oncology Center under the tutelage of Dr. Bert Vogelstein, the award sponsor. Colorectal cancer is chosen for inquiry in part because it is the second most common cause of cancer deaths in the United States. A long range goal of Dr. Vogelstein's laboratory program is to locate, clone, sequence, and characterize the function of putative colorectal tumor suppressor genes. Deletions of putative tumor suppressor genes on chromosome 17 and 18 are observed in over 70% of human colorectal carcinomas. Dr. Simon's research will focus on cloning a putative colorectal tumor suppressor gene in phase I. Restriction length polymorphism analysis has allowed identification of a relatively small region within chromosome 18 alpha that encompasses the putative suppressor gene. Chromosome walking techniques will be used to identify expressed sequences within this region. cDNA libraries will be screened to isolate candidate suppressor genes containing expressed sequences. The wide range of molecular genetic techniques necessary to conduct these studies will guarantee a rigorous education in molecular biology. Successful implementation of these studies should provide a fertile area of research for phase II. Phase I of the award will also encompass a didactic program in molecular biology. A faculty advisory committee of four senior basic scientists, chaired by the sponsor, will review a written research progress report and seminar presented every four months. Dr. Simons will also attend eight formal graduate courses with the Department of Molecular Biology and Genetics at the Johns Hopkins University School of Medicine. Having satisfactorily completed phase I, Dr. Simons will assume a faculty position to pursue these studies further in phase II.